Mercury (Hg) is a widespread environmental agent whose toxic potential to numerous organ systems including the immune system has been well-recognized. The immunotoxicity of Hg is complex involving on the one hand immunosuppression, yet on the other hand immunopotentiation. It is perhaps Hg's immunostimulatory aspects that are most relevant and significant with respect to adverse human health effects. The conceptual framework that this proposal is built around is that Hg is an environmental agent that contributes to the development of autoimmune disease. Animal studies have established a connection between experimental exposure to Hg and lupus-like autoimmune disease. Similarly, case reports demonstrating a correlation between accidental Hg exposure and either the onset or the severity of autoimmune disease symptoms support a link between Hg intoxication and the etiology of human autoimmune disease. From this perspective, Hg is one of the few suspected environmental agents where a link between exposure to the agent and autoimmune disease has been indicated. However, the mechanisms whereby Hg initiates, potentiates, or perpetuates autoimmune responses have not been established. In particular, there is a dearth of information regarding the biochemical/molecular mechanisms involved in mercury-mediated autoimmunity. Accordingly, the long-term goal of this proposal is to identify biochemical/molecular mechanisms underlying-mercury-mediated autoimmune disease. In that recent work from our laboratories have established that noncytotoxic concentrations of inorganic mercury interfere with the CD95 apoptotic signaling pathway and that low concentrations of inorganic mercury interfere with protein tyrosine mediated signaling, our research focuses on lymphocyte signaling pathways involved in the regulation of CD95-induced apoptosis. Since CD95-mediated apoptosis is involved in the regulation of peripheral tolerance, dysregulation of CD95-signaling by Hg may be one of many factors, either genetic or environmental, contributing to autoimmune disease incidence. The hypothesis guiding the proposal is that inorganic mercury disrupts CD95-mediated apoptosis, which contributes to a breakdown in peripheral tolerance to autoantigens leading to the development of autoimmune disease. The perspective for formulating this hypothesis stems from the view that autoimmune diseases represent an accumulation of autoreactive lymphocytes due to defects in apoptotic death. The hypothesis will be tested using cell lines and activated human CD4 positive lymphoblasts, where the influences of low concentrations of inorganic Hg on 1) components of the CD95 apoptotic machinery and 2) cross talk between nonreceptor kinase signaling pathways and the CD95 pathway will be determined. A third specific aim will employ a mouse model to establish whether disruption of CD95-mediated cell death by mercury intoxication in vivo enhances the survival of autoreactive T lymphocytes.